DOSI measurements of breast tumour response to NAC provide quantitative functional indices derived from spectroscopic features. DOSI information content changes throughout the course of treatment in proportion to the degree of pathological response. As shown in previous studies, T/N ratios of both the TOI and deoxyhaemoglobin concentration (ctHHb) correlate best with the degree of pathological response determined by standard surgical pathology [38
]. The degree of TOI change stratified by pCR/non-pCR was statistically significant by the midpoint of therapy (Z
=0.011), and was not statistically significant for ctHHb at the same timepoint (Z
=0.062). Similar results have been observed using PET and MRS [23
]. Both TOI and ctHHb were statistically significant by the conclusion of therapy.
Our current study results fit within the context of previous work. Direct comparison between studies is difficult because of the difference in measured timepoints and optical parameters. We previously reported that both ctHHb and ctH2
O decreased significantly in pathological responders after one week of A/C therapy [38
]. These decreases are consistent with the TOI decreases (which are proportional to ctHHb and ctH2
O) observed in this study; however, we note that the measurement timepoints differed (one week post-therapy versus therapy midpoint). A detailed case study demonstrating that TOI decreases in response to NAC revealed a TOI-T/N drop in a partial responder (non-pCR) of about 30 per cent by therapy midpoint, which is consistent with the average 20 per cent drop reported here [50
]. Soliman et al
] reported that ctHHb and ctO2
Hb decreased significantly in stronger pathological responders after four weeks of chemotherapy; ctH2
O also decreased but not significantly when compared with poor responders. We note that these studies used a tomographic method to image larger tumours and subjects did not achieve pCR (N
=10). Despite differences in patient population and imaging approach, the results of Soliman et al
] are consistent with our findings.
DOSI measurements of endogenous tissue haemoglobin, water and lipids are indicators of important metabolic alterations in tumours that may well complement current efforts to assess breast tumour response. Because DOSI measures several functional contrast elements related to cellular metabolism, angiogenesis and extracellular matrix, NIR optical methods have the potential to provide important functional information related to tumour regression [38
]. Given these functional sensitivities, we have adopted terminology used in the MRI/MRS community and suggest the term ‘optical imaging biomarker’, where ‘biomarker’ applies to ‘any detectable biological parameter, whether biochemical, genetic, histologic, anatomic, physical, functional or metabolic’ [51
]. Optical biomarkers are in reality ‘pre-biomarkers’ because they are at the ‘proof of concept’ stage [51
]. Although DOSI parameters lack the specificity of gene- or protein-based biomarkers, optical imaging measures endogenous biochemical composition and tumour pathological state. A more complete understanding of the relationship between optical imaging biomarkers and classical biomarkers (e.g. Ki67) or therapeutic endpoints (e.g. pathological response) is an important area of future research.
Therapeutic drug monitoring in the neoadjuvant setting is an ideally suited application for diffuse optical methods because it accentuates the strengths (functional, portable) and offsets the limitations (low spatial resolution) of the technique. DOSI resolution limits are a consequence of multiple-light scattering in a relatively large sample volume, providing macroscopically averaged tissue absorption and scattering properties at depths up to several centimetres. Consequently, the resolution of DOSI methods is of the order of a few transport scattering lengths (approx. 5 mm to 1
cm), which is similar to PET. However, the potential limitations of DOSI in localizing small lesions are not important in characterizing NAC response in large, palpable stage II–IV tumours. This is because DOSI is inherently a functional imaging technique that is highly sensitive to endogenous biochemical composition and tumour pathological response [38
Because of its portability and low cost, the bedside DOSI platform used in this study is a low barrier-to-access technology. As such, it potentially creates new opportunities for patients to receive personalized treatment and for physicians to gain insights into mechanisms of cancer appearance and response to therapy. An important practical advantage of our DOSI approach is that it can be used frequently in unconventional settings such as a doctor's surgery or clinic. Portable optical imaging platforms can easily supplement existing radiological methods either as standalone devices or as units integrated into established technologies such as ultrasound, mammography or MRI [40
Although the results of this study are encouraging, some limitations should be noted: two are study design limitations and two others are DOSI limitations. With regard to study design limitations, the study was non-blinded; pathological results were known at the time of analysis and thus the results should be considered correlative and not predictive. For this reason, although the separation of pCR from non-pCR was statistically significant, we have not calculated sensitivity/specificity or receiver operating characteristic (ROC) curve performance. In addition, the optical–physiological responses were not placed within the context of other emerging therapeutic assessment techniques (i.e. MRI, PET, genomic/biomarker profiles); only standard of care surgical pathology was used. Thus, the functional interpretation of TOI changes in response to therapy was based on the relationship between tissue optical properties and conventional histological measures. In the future, the combination of DOSI with tissue and/or blood biomarkers could potentially improve overall predictive power [38
With regard to DOSI limitations, the entire tumour volume was not imaged, which can result in a ‘partial volume’ effect. NIR photons are heavily attenuated by the large blood volume of tumours, and combined with a single spatial view (i.e. non-tomographic) the tumour underside was not sampled. Because of this limitation, spatially localized pockets of non-responding tumour volume (i.e. heterogeneity) are currently difficult to detect. Improved imaging capabilities may further stratify pPR from pCR. We note that, because we have not employed a tomographic approach, the absolute values of the tumour optical properties depend upon the depth and size on the lesion. We have shown that the extreme values of DOSI measurements are not strongly dependent on tumour size [42
], but DOSI absolute values are dependent on tumour depth. However, this limited imaging capability should be balanced against the simplicity of the data acquisition. Continued DOSI technical developments will improve imaging capabilities and minimize this effect. Furthermore, none of the quantities measured are specific for cancer; thus thresholded changes (which are commonly employed in PET) may not reveal true residual disease. Recent discovery of malignancy-specific optical absorption signatures may help in this regard [54
In order to standardize and coordinate rapidly advancing breast optical methods, a multi-institutional NCI Network for Translational Research in Optical Imaging (NTROI, U54CA105480) was established in 2003. The NTROI helped to build a consensus on NAC monitoring as a primary clinical focus area, and provided guidelines for quantitative image analysis and instrument calibration [53
]. The results of this study are an expanded effort relative to initial case studies involving optical methods to track breast tumour response to therapy in human subjects. A prospective multi-centre clinical trial is in development in partnership with the American College of Radiology Imaging Networks (ACRIN-6691) that will employ identical DOSI instruments.